Life Sciences Commons^™

Sensitization Of Human Cancer Cells To Gemcitabine By The Chk1 Inhibitor Mk-8776: Cell Cycle Perturbation And Impact Of Administration Schedule In Vitro And In Vivo, Ryan Montano, Ruth Thompson, Injae Chung, Huagang Hou, Nadeem Khan, Alan Eastman

Dartmouth Scholarship

Chk1 inhibitors have emerged as promising anticancer therapeutic agents particularly when combined with antimetabolites such as gemcitabine, cytarabine or hydroxyurea. Here, we address the importance of appropriate drug scheduling when gemcitabine is combined with the Chk1 inhibitor MK-8776, and the mechanisms involved in the schedule dependence.

Divergent Antibody Subclass And Specificity Profiles But Not Protective Hla-B Alleles Are Associated With Variable Antibody Effector Function Among Hiv-1 Controllers, Jennifer I. Lai, Anna F. Licht, Anne-Sophie Dugast, Todd Suscovich, Ickwon Choi, Chris Bailey-Kellogg, Galit Alter, Margaret E. Ackerman

Dartmouth Scholarship

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector …

Integrating Human Omics Data To Prioritize Candidate Genes., Yong Chen, Xuebing Wu, Rui Jiang

Faculty Scholarship for the College of Science & Mathematics

BACKGROUND: The identification of genes involved in human complex diseases remains a great challenge in computational systems biology. Although methods have been developed to use disease phenotypic similarities with a protein-protein interaction network for the prioritization of candidate genes, other valuable omics data sources have been largely overlooked in these methods.

METHODS: With this understanding, we proposed a method called BRIDGE to prioritize candidate genes by integrating disease phenotypic similarities with such omics data as protein-protein interactions, gene sequence similarities, gene expression patterns, gene ontology annotations, and gene pathway memberships. BRIDGE utilizes a multiple regression model with lasso penalty to …

Identifying Potential Cancer Driver Genes By Genomic Data Integration., Yong Chen, Jingjing Hao, Wei Jiang, Tong He, Xuegong Zhang, Tao Jiang, Rui Jiang

Faculty Scholarship for the College of Science & Mathematics

Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis …

Contrast Negation Differentiates Visual Pathways Underlying Dynamic And Invariant Facial Processing, Pamela M. Pallett, Ming Meng

Dartmouth Scholarship

Abstract Bruce and Young (1986) proposed a model for face processing that begins with structural encoding, followed by a split into two processing streams: one for the dynamic aspects of the face (e.g., facial expressions of emotion) and the other for the invariant aspects of the face (e.g., gender, identity). Yet how this is accomplished remains unclear. Here, we took a psychophysical approach using contrast negation to test the Bruce and Young model. Previous research suggests that contrast negation impairs processing of invariant features (e.g., gender) but not dynamic features (e.g., expression). In our first experiment, participants discriminated differences in …

Definition Of An Hla-Dpw2-Restricted Epitope On Ns3, Recognized By A Dengue Virus Serotype-Cross-Reactive Human Cd4+ Cd8- Cytotoxic T-Cell Clone, Ichiro Kurane, Li Chen Dai, Peter G. Livingston, Elaine Reed, Francis A. Ennis

Li Dai

We previously reported that the clone JK34 was cross-reactive for dengue virus types 1, 2, 3, and 4 and recognized NS3 (I. Kurane, M. A. Brinton, A. L. Samson, and F. A. Ennis, J. Virol. 65:1823-1828, 1991). In the present experiments, we defined the epitope at the amino acid level, with 93 15-mer overlapping peptides which cover the entire NS3. A peptide 4 which contains amino acids 251 to 265 of NS3 sensitized the autologous B lymphoblastoid cell line (LCL) to the lysis by JK34. The smallest peptide recognized by JK34 was a 10-mer peptide which contains amino acids 255 …

Mutation Of Human Immunodeficiency Virus Type 1 At Amino Acid 585 On Gp41 Results In Loss Of Killing By Cd8+ A24-Restricted Cytotoxic T Lymphocytes, Li Chen Dai, Kim West, Rebecca A. Littaua, Kazuo Takahashi, Francis A. Ennis

Li Dai

A human leukocyte antigen A24-restricted CD8+ cytotoxic T-cell clone specific for gp41 of human immunodeficiency virus type 1 was isolated from an infected individual. The epitope was localized to amino acids 584 to 591 (YLKDQQLL, NL43 env sequence) of gp41 by using a panel of recombinant vaccinia viruses that contain truncated env genes and synthetic peptides. The clone killed autologous B-lymphoblastoid cell lines pulsed with a synthetic peptide reflecting the sequence of the IIIB and MN strains. This clone, however, failed to kill target cells pulsed with the peptides that have a mutation from Lys to Arg or Gln at …

Analgesic Tolerance Of Opioid Agonists In Mutant Mu-Opioid Receptors Expressed In Sensory Neurons Following Intrathecal Plasmid Gene Delivery, Guangwen Li, Fei Ma, Yanping Gu, Li-Yen Mae Huang

Physiology Faculty Publications

Background: Phosphorylation sites in the C-terminus of mu-opioid receptors (MORs) are known to play critical roles in the receptor functions. Our understanding of their participation in opioid analgesia is mostly based on studies of opioid effects on mutant receptors expressed in in vitro preparations, including cell lines, isolated neurons and brain slices. The behavioral consequences of the mutation have not been fully explored due to the complexity in studies of mutant receptors in vivo. To facilitate the determination of the contribution of phosphorylation sites in MOR to opioid-induced analgesic behaviors, we expressed mutant and wild-type human MORs (hMORs) in sensory …

The Gating Charge Should Not Be Estimated By Fitting A Two-State Model To A Q-V Curve, Francisco Bezanilla, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

The voltage dependence of charges in voltage-sensitive proteins, typically displayed as charge versus voltage (Q-V) curves, is often quantified by fitting it to a simple two-state Boltzmann function. This procedure overlooks the fact that the fitted parameters, including the total charge, may be incorrect if the charge is moving in multiple steps. We present here the derivation of a general formulation for Q-V curves from multistate sequential models, including the case of infinite number of states. We demonstrate that the commonly used method to estimate the charge per molecule using a simple Boltzmann fit is not only inadequate, but in …

X-Linked Mtmr8 Diversity And Evolutionary History Of Sub-Saharan Populations, Damian Labuda, Vania Yotova, Jean-François Lefebvre, Claudia Moreau, Gerd Utermann, Scott M. Williams

Dartmouth Scholarship

The genetic diversity within an 11 kb segment of the MTMR8 gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary …

On The Evolution Of The Serotonin Transporter Linked Polymorphic Region (5-Httlpr) In Primates, Seth D. Dobson, Lauren J.N Brent

Dartmouth Scholarship

Some allelic variants of the serotonin transporter linked polymorphic region (5-HTTLPR) result in lower levels of expression of the serotonin transporter gene (SLC6A4). These low-expressing (LE) alleles are associated with mental-health disorders in a minority of humans that carry them. Humans are not the only primates that exhibit this polymorphism; other species, including some monkeys, also have LE and high-expressing (HE) variants of 5-HTTLPR. We propose a behavioral genetic framework to explain the adaptive evolution of this polymorphism in primates, including humans. We hypothesize that both LE and HE alleles are maintained by balancing selection in species characterized …

Socially Excluded Individuals Fail To Recruit Medial Prefrontal Cortex For Negative Social Scenes, Katherine E. Powers, Dylan D. Wagner, Catherine J. Norris, Todd F. Heatherton

Dartmouth Scholarship

Converging behavioral evidence suggests that people respond to experiences of social exclusion with both defensive and affiliative strategies, allowing them to avoid further distress while also encouraging re-establishment of positive social connections. However, there are unresolved questions regarding the cognitive mechanisms underlying people's responses to social exclusion. Here, we sought to gain insight into these behavioral tendencies by using functional magnetic resonance imaging (fMRI) to examine the impact of social exclusion on neural responses to visual scenes that varied on dimensions of sociality and emotional valence. Compared to socially included participants, socially excluded participants failed to recruit dorsomedial prefrontal cortex …

The Composite Effect For Inverted Faces Is Reliable At Large Sample Sizes And Requires The Basic Face Configuration, Tirta Susilo, Constantin Rezlescu, Bradley Duchaine

Dartmouth Scholarship

Abstract The absence of the face composite effect (FCE) for inverted faces is often considered evidence that holistic processing operates only on upright faces. However, such absence might be explained by power issues: Most studies that have failed to find the inverted FCE tested 24 participants or less. Here we find that the inverted FCE exists reliably when we tested at least 60 participants. The inverted FCE was ∼ 18% the size of the upright FCE, and it was unaffected by testing order: It did not matter whether participants did the upright condition first (Experiment 1, n = 64) or …

Recurrent Tissue-Specific Mtdna Mutations Are Common In Humans, David C. Samuels, Chun Li, Bingshan Li, Zhuo Song, Eric Torstenson, Hayley Boyd Clay, Antonis Rokas, Tricia A. Thornton-Wells, Jason H. Moore, Tia M. Hughes, Robert D. Hoffman, Jonathan L. Haines, Deborah G. Murdock, Douglas P. Mortlock, Scott M. Williams

Dartmouth Scholarship

Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in …

Adam17-Mediated Processing Of Tnf-Α Expressed By Antiviral Effector Cd8+ T Cells Is Required For Severe T-Cell-Mediated Lung Injury, Matthew P. Deberge, Kenneth H. Ely, Guang-Shing Cheng, Richard I. Enelow

Dartmouth Scholarship

Influenza infection in humans evokes a potent CD8+ T-cell response, which is important for clearance of the virus but may also exacerbate pulmonary pathology. We have previously shown in mice that CD8+ T-cell expression of TNF-a is required for severe and lethal lung injury following recognition of an influenza antigen expressed by alveolar epithelial cells. Since TNF-a is first expressed as a transmembrane protein that is then proteolytically processed to release a soluble form, we sought to characterize the role of TNF-a processing in CD8+ T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF-a by …

Sensing Charges Of The Ciona Intestinalis Voltage-Sensing Phosphatase, Carlos A. Villalba-Galea, Ludivine Frezza, Walter Sandtner, Francisco Bezanilla

School of Pharmacy Faculty Articles

Voltage control over enzymatic activity in voltage-sensitive phosphatases (VSPs) is conferred by a voltage-sensing domain (VSD) located in the N terminus. These VSDs are constituted by four putative transmembrane segments (S1 to S4) resembling those found in voltage-gated ion channels. The putative fourth segment (S4) of the VSD contains positive residues that likely function as voltage-sensing elements. To study in detail how these residues sense the plasma membrane potential, we have focused on five arginines in the S4 segment of the Ciona intestinalis VSP (Ci-VSP). After implementing a histidine scan, here we show that four arginine-to-histidine mutants, namely R223H to …

Epigenetic Dominance Of Prion Conformers, Eri Saijo, Hae-Eun Kang, Jifeng Bian, Kristi G. Bowling, Shawn Browning, Sehun Kim, Nora Hunter, Glenn C. Telling

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP) primary structures interact with distinct prion conformations to influence pathogenesis, …

Killerflip: A Novel Lytic Peptide Specifically Inducing Cancer Cell Death, B Pennarun, G. Gaidos, O Bucur, A Tinari

Dartmouth Scholarship

One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killer FLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using …

Speed Is Relative (Human And Animal Running Speeds): Are You A Cheetah, A Chicken, Or A Snail?, Chad E. Buckley

Faculty and Staff Publications – Milner Library

To put matters in perspective, running speeds for humans and other land animals are compared over various distances. Humans compare quite favorably over longer distances with many species. Both fast and slow human runners can benefit from comparing their individual times in races with other species.

An Expanded View Of The Eukaryotic Cytoskeleton, James B. Moseley

Dartmouth Scholarship

A rich and ongoing history of cell biology research has defined the major polymer systems of the eukaryotic cytoskeleton. Recent studies have identified additional proteins that form filamentous structures in cells and can self-assemble into linear polymers when purified. This suggests that the eukaryotic cytoskeleton is an even more complex system than previously considered. In this essay, I examine the case for an expanded definition of the eukaryotic cytoskeleton and present a series of challenges for future work in this area.

Accommodations For Patients With Disabilities In Primary Care: A Mixed Methods Study Of Practice Administrators, Jennifer Renee Pharr

Environmental & Occupational Health Faculty Publications

Structural barriers that limit access to health care services for people with disabilities have been identified through qualitative studies; however, little is known about how patients with disabilities are accommodated in the clinical setting when a structural barrier is encountered. The purpose of this study was to identify how primary care medical practices in the United States accommodated people with disabilities when a barrier to service is encountered. Primary care practice administrators from the medical management organization were identified through the organization’s website. Sixty-three administrators from across the US participated in this study. Practice administrators reported that patients were examined …

A Population-Based Case–Control Study Of Urinary Arsenic Species And Squamous Cell Carcinoma In New Hampshire, Usa, Diane Gilbert-Diamond, Zhigang Li, Ann E. Perry, Steven K. Spencer, A Jay Gandolfi, Margaret R. Karagas

Dartmouth Scholarship

Background: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States.

Objective: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population.

Methods: We conducted a population-based case–control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and …

Pathoscope: Species Identification And Strain Attribution With Unassembled Sequencing Data., Owen E Francis, Matthew Bendall, Solaiappan Manimaran, Changjin Hong, Nathan L Clement, Eduardo Castro-Nallar, Quinn Snell, G Bruce Schaalje, Mark J Clement, Keith A Crandall, W Evan Johnson

Computational Biology Institute

Emerging next-generation sequencing technologies have revolutionized the collection of genomic data for applications in bioforensics, biosurveillance, and for use in clinical settings. However, to make the most of these new data, new methodology needs to be developed that can accommodate large volumes of genetic data in a computationally efficient manner. We present a statistical framework to analyze raw next-generation sequence reads from purified or mixed environmental or targeted infected tissue samples for rapid species identification and strain attribution against a robust database of known biological agents. Our method, Pathoscope, capitalizes on a Bayesian statistical framework that accommodates information on sequence …

Identification Of Cell Cycle–Regulated Genes Periodically Expressed In U2os Cells And Their Regulation By Foxm1 And E2f Transcription Factors, Gavin D. Grant, Lionel Brooks Iii, Xiaoyang Zhang, J. Matthew Mahoney, Viktor Martyanov, Tammara A. Wood, Gavin Sherlock, Chao Cheng, Michael L. Whitfield

Dartmouth Scholarship

We identify the cell cycle–regulated mRNA transcripts genome-wide in the osteosarcoma-derived U2OS cell line. This results in 2140 transcripts mapping to 1871 unique cell cycle–regulated genes that show periodic oscillations across multiple synchronous cell cycles. We identify genomic loci bound by the G2/M transcription factor FOXM1 by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) and associate these with cell cycle–regulated genes. FOXM1 is bound to cell cycle–regulated genes with peak expression in both S phase and G2/M phases. We show that ChIP-seq genomic loci are responsive to FOXM1 using a real-time luciferase assay in live cells, showing that FOXM1 strongly …

The Flexible Fairness: Equality, Earned Entitlement, And Self-Interest, Chunliang Feng, Yi Luo, Ruolei Gu, Lucas S. Broster, Xueyi Shen, Tengxiang Tian, Yue-Jia Luo, Frank Krueger

Behavioral Science Faculty Publications

The current study explored whether earned entitlement modulated the perception of fairness in three experiments. A preliminary resource earning task was added before players decided how to allocate the resource they jointly earned. Participants' decision in allocation, their responses to equal or unequal offers, whether advantageous or disadvantageous, and subjective ratings of fairness were all assessed in the current study. Behavioral results revealed that participants proposed more generous offers and showed enhanced tolerance to disadvantageous unequal offers from others when they performed worse than their presumed "partners," while the reverse was true in the better-performance condition. The subjective ratings also …

Aspirin And Low-Molecular Weight Heparin Combination Therapy Effectively Prevents Recurrent Miscarriage In Hyperhomocysteinemic Women., Pratip Chakraborty, Sayani Banerjee, Piyali Saha, Shyam Sundar Nandi, Sunita Sharma, Sourendra K. Goswami, Baidyanath Chakravarty, Syed N. Kabir

Journal Articles: Cellular & Integrative Physiology

The management of recurrent pregnancy loss (RPL) still remains a great challenge, and women with polycystic ovarian syndrome (PCOS) are at a greater risk for spontaneous abortion. Treatment with low-molecular-weight heparin (LMWH) has become an accepted treatment option for women with RPL; however, the subgroup of women, who are likely to respond to LMWH, has not been precisely identified. The present study evaluated the efficacy of LMWH with reference to PCOS and associated metabolic phenotypes including hyperhomocysteinemia (HHcy), insulin resistance (IR) and obesity. This prospective observational study was conducted at Institute of Reproductive Medicine, Kolkata, India. A total of 967 …

Self-Regulatory Depletion Increases Emotional Reactivity In The Amygdala, Dylan D. Wagner, Todd F. Heatherton

Dartmouth Scholarship

The ability to self-regulate can become impaired when people are required to engage in successive acts of effortful self-control, even when self-control occurs in different domains. Here, we used functional neuroimaging to test whether engaging in effortful inhibition in the cognitive domain would lead to putative dysfunction in the emotional domain. Forty-eight participants viewed images of emotional scenes during functional magnetic resonance imaging in two sessions that were separated by a challenging attention control task that required effortful inhibition (depletion group) or not (control group). Compared to the control group, depleted participants showed increased activity in the left amygdala to …

Bioengineered Lysozyme Reduces Bacterial Burden And Inflammation In A Murine Model Of Mucoid Pseudomonas Aeruginosa Lung Infection, Charlotte C. Teneback, Thomas C. Scanlon, Matthew J. Wargo, Jenna L. Bement, Karl E. Griswold, Laurie W. Leclair

Dartmouth Scholarship

The spread of drug-resistant bacterial pathogens is a growing global concern and has prompted an effort to explore potential adjuvant and alternative therapies derived from nature's repertoire of bactericidal proteins and peptides. In humans, the airway surface liquid layer is a rich source of antibiotics, and lysozyme represents one of the most abundant and effective antimicrobial components of airway secretions. Human lysozyme is active against both Gram-positive and Gram-negative bacteria, ac

A Unified Framework Integrating Parent-Of-Origin Effects For Association Study, Feifei Xiao, Jianzhong Ma, Christopher I. I. Amos

Dartmouth Scholarship

Genetic imprinting is the most well-known cause for parent-of-origin effect (POE) whereby a gene is differentially expressed depending on the parental origin of the same alleles. Genetic imprinting is related to several human disorders, including diabetes, breast cancer, alcoholism, and obesity. This phenomenon has been shown to be important for normal embryonic development in mammals. Traditional association approaches ignore this important genetic phenomenon. In this study, we generalize the natural and orthogonal interactions (NOIA) framework to allow for estimation of both main allelic effects and POEs. We develop a statistical (Stat-POE) model that has the orthogonal estimates of parameters including …

Treatment With Monoclonal Antibodies Against Clostridium Difficile Toxins, Israel Lowy, Deborah Molrine, Brett Leav, Barbara Blair, Roger Baxter, Dale Gerding, Geoffrey Nichol, William Thomas, Mark Leney, Susan Sloan, Catherine Hay, Donna Ambrosino

William D Thomas Jr

BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection.

METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.

RESULTS: …